Intracellular polymerization of deoxyhemoglobin S is the basis for the pathophysiology of sickle cell anemia. We found that intracellular polymer can be detected at high oxygen saturation (greater than 90%) in SS erythrocytes as measured by double nuclear magnetic resonance and increased with decreasing oxygen saturation, in general agreement with theoretical calculations. Intracellular polymer is now being measured in SS erythrocytes separated on the basis of corpuscular hemoglobin concentration. The small difference in intracellular polymer formation between whole SS cell populations and the more uniform fractionated subpopulation at the same MCHC represents the contribution from cell heterogeneity. In our studies on the other sickle syndromes, polymer in SC erythrocytes is detected below 70% oxygen saturation, following more closely the behavior of AS than SS erythrocytes. Although hemoglobin C behaves like hemoglobin A in copolymerization with hemoglobin S, the relative clinical severity of SC disease compared with benign AS can be attributed to an increase in MCHC with a substantial increase of cells with MCHC greater than 40 g/dl. Further, our polymer calculations for the sickle syndromes correlates well with hemolytic anemia as measured by total hemoglobin.